Traumatic brain injury (TBI) is a hallmark injury to soldiers on the battlefield in Iraq and Afghanistan and thus represents a major health issue for veterans returning from these wars. New therapies are urgently needed to prevent brain damage from TBI, improve functional outcomes, and reduce the enhanced risk of dementia associated with TBI. In this application, we propose that NADPH oxidase, a membrane enzyme that generates the highly reactive and damaging free radical superoxide, plays a critical role in cortical and hippocampal damage, cognitive decline, increased risk of dementia, and emotional dysfunction following TBI. We further propose that therapies targeted at inhibiting NADPH oxidase activation, or its key upstream and downstream, mediators will have significant efficacy in the treatment of TBI in veterans. Specific Aim 1 would perform preclinical studies to determine the efficacy of NADPH oxidase inhibitors in exerting neuroprotection and improving functional outcome after TBI. This aim would determine what are the therapeutic window, optimal dose, and optimal NADPH oxidase inhibitor for translation to the clinic. Specific Aim 2 would determine the role of the upstream factors, PTEN and Rac1 in NOX2 NADPH oxidase activation and TBI pathology, and explore their utility as potential novel upstream therapeutic targets in TBI. There are no studies on either Rac1 and PTEN in TBI, and thus the studies are highly novel. Rac1 activation is required for NOX2 activation, and thus targeting it for inhibition could lead to powerful neuroprotection and improved functional outcome in TBI. PTEN is a critical negative regulator of Akt, a well known pro-survival factor. Targeting PTEN for inhibition would thus offer a novel and potentially robust mechanism for enhanced pro-survival signaling following TBI. Specific Aim 3 would establish the role of JNK-Jun signaling in mediating NADPH oxidase-induced pathology following TBI. We propose that NADPH oxidase-induced up-regulation of AD-related proteins and resultant neurodegeneration is achieved via both transcriptional and post- translational mechanisms that are mediated by downstream JNK-Jun signaling. NOX2 knockout mice and NADPH oxidase inhibitor studies will be used to determine the regulatory role of NOX2 on JNK/Jun signaling pathway induction after TBI. JNK inhibition will also be used to determine the role of JNK/Jun signaling in AD-related protein induction, neurodegeneration and functional outcome following TBI. As a whole, the studies will enhance our understanding of the pathological mechanisms underlying TBI, and have the potential to yield important new therapies for TBI.